A Novel Self-Recognizing And Dual-Responsive Carrier-Free Phototheranostic Nanoagents For Photoacoustic/Fluorescence Imaging-Guided Synergistic Photothermal-Chemotherapy In Small-Cell Lung Cancer

Small-cell lung cancer(SCLC)is one of the most common malignant tumors.The morbidity and mortality of SCLC are not optimistic in our country.Although nanoagents have attracted more and more attention in recent years,the lack of tumor targeting and low drug payload severely impeded various nanoagents further used in SCLC.Consequently,how to develop new targeting ligand and enhance drug payload had been an urgent need for SCLC treatment.Herein,we firstly sifted and verified that capreomycin(Cm)had a high affinity for CD56 receptors overexpressed on SCLC cells.Motivated by the concept of targeted drug delivery,Cm was selected as the specific targeting ligand towards CD56 receptors and chemo-drug doxorubicin(Dox)was adopted to be covalently linked via the redox-responsive disulfide linkage.The synthesized self-targeting conjugate(Dox-ss-Cm)and FDA-approved photosensitizer indocyanine green(ICG)as structural motifs could be self-assembled into nanoparticles(ICG@Dox-ss-Cm NPs)in aqueous solution.ICG@Dox-ss-Cm NPs were confirmed by the transmission electron microscope(TEM)that the nanoagents were uniform and stable with the particle size of smaller than 200nm.In vitro release experiments showed that such carrier-free nanoagents with high drug payload could exert targeted ondemand drug release under dual stimuli of glutathione(GSH)and external NIR.In vitro cellular uptake experiments,in vitro antitumor activity experiments and in vivo multiple bioimaging experiments further confirmed that ICG@Dox-ss-Cm NPs could be specifically self-recognized via SCLC cells in vitro and self-targeted to SCLC sites in vivo,thus decreasing the undesirable effects to normal tissues and organs.Further in vivo antitumor activity experiments consistently confirmed that such nanoagents showed highly synergistic photothermal-chemotherapy for SCLC under the guidance of fluorescence/photoacoustic imaging.Taken together,this project could provide a novel,simple,flexible strategy for targeted treatment of SCLC.